The HPV cancer vaccine: Are two doses as good as three?

Regarding the three-dose HPV vaccine, the sticking point is getting tweens and teens to make it through all three doses before they become sexually active – and exposed to a virus that might eventually morph into cervical or anogenital cancer.

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How do you get more people to take advantage of the cancer-busting HPV vaccine?

One way might be to lower the number of doses, a hot topic among public health researchers attending HPV2014, the 29th International Papillomavirus Conference, which came to a close Monday in Seattle.

“Everything indicates that we will go from a three-dose program to a two-dose program,” said Dr. Silvina Arrossi, head of the National Program for Cervical Cancer in Argentina. “If reducing [the dose] is just as effective, it’s a very good idea from a public health point of view. For adherence, for the cost – everything is simplified.”

The three-dose HPV vaccine, introduced in the U.S. in 2006, has been shown to be almost 100 percent effective in preventing four human papillomavirus types, which affect nearly all sexually active men and women at some point in their lives.

The sticking point is getting tweens and teens to make it through all three doses of the vaccine before they become sexually active – and exposed to a virus that might eventually morph into cervical or anogenital cancer.

CDC: Adherence rates ‘unacceptably low’

In July, the Centers for Disease Control and Prevention called adherence rates in the U.S. “unacceptably low,” citing a report that showed only 38 percent of teen girls and 14 percent of teen boys finished the three-dose series. The adherence rate for one dose was 57 percent for girls and 35 percent for boys.

“All of the clinical trials have been done using three doses, but there are some trials that are ongoing now looking at two versus three doses,” said Fred Hutch’s Dr. Denise Galloway, whose research demonstrated the link between HPVs and nearly all genital tract cancers and helped pave the way for the HPV vaccine.

“There are two studies that have been published and there’s some observational data from people who don’t complete their three doses but have one or two doses, and it shows a lot of efficacy,” she said. “So WHO went ahead and made the recommendation that for 9- to 11-year-old girls who respond well to vaccine, it is sufficient to go to two doses.”

Timing is everything

In the U.S., pre-adolescent boys and girls get their first dose at month “zero,” their second dose two months after that and their third and final dose six months after the first one.

Galloway noted that for a two-dose schedule to be as effective, it has to be timed just right.

“The normal schedule is zero-two-six [months zero, two and six] but if you just take zero and two, that’s not as good,” she said. “You need a longer interval between the two doses to develop a memory response. WHO has shown that if you have [the vaccine at month] zero and then at six months, that it should be OK.”

She also emphasized that the two-dose schedule is not yet approved in the U.S.

“That’s a big consideration,” she said. “Will the FDA [Food and Drug Administration] go for a two-dose schedule? There are a number of countries that say they approve, but not all of them have started using it. Economically, of course it’s going to be cheaper.”

Efficacy, however, trumps all, she said.

“You want to extrapolate and say, what’s going to happen to 25-year-olds?” she said. “Are they going to be protected with two doses if they get vaccinated at 10? Fifteen years later, are they still protected? We don’t know that. So it’s a big gamble.”

According to the WHO recommendation, Galloway said, a two-dose prime boost strategy – including at least six months between the first and the second dose – is expected to provide similar protection compared to a three-dose regimen.

Reduced costs and better adherence were cited as prime reasons for the switch. But, like Galloway, WHO also emphasized the need for more research.

“There are fewer data comparing the efficacy of two- versus three-dose schedules,” WHO’s Strategic Advisory Group of Experts (SAGE) wrote in its recommendation. “Longer term studies are underway.”

The University of British Columbia’s Dr. Simon Dobson, who authored a 2013 paper on the effectiveness of two versus three doses of the HPV vaccine, spoke on Sunday about the sea change in HPV dosage.

“[Ours] wasn’t the only study going on around two doses,” he said. “GSK [GlaxoSmithKline, maker of Cervarix] launched their own very carefully planned series of studies that led to licensure for two doses of the bivalent vaccine.”

A bivalent HPV vaccine protects against two strains of virus while a quadrivalent vaccine protects against four. Two such vaccines are currently licensed by the FDA. Cervarix, a bivalent vaccine, prevents against HPV16 and 18, which cause 70 percent of cervical cancers. Gardasil, a quadrivalent vaccine, prevents against HPV16 and 18, as well as HPV6 and 11, which cause 90 percent of genital warts. Gardasil, the only vaccine licensed for use in males, also has been shown to protect against cancers of the anus, vagina and vulva.

Galloway said she was particularly excited about several abstracts presented at HPV2014 that describe trials with a nine-valent vaccine that could protect more than 92 percent of HPV-associated cancers.

Two-dose vaccine going global

Dobson said that in the European Union, the two-dose HPV vaccine series has been approved for Cervarix for females aged 9 to 14 and for Gardasil for males and females aged 9 to 13. A two-dose system has also been approved in Bangladesh, Pakistan, the Philippines, Ghana, Nigeria, South Africa, El Salvador, Guyana, Haiti, Panama, Brazil, Colombia, Chile, Guatemala and other countries.

“There are many countries on different continents where the approval has been given for a two-dose series, both bivalents and quadrivalents,” said Dobson. “This list [of countries] is getting longer by the day.“

Research around dosing – and adherence issues – continues to grow, as well.

Dobson is currently in the middle of an effectiveness study comparing two versus three doses in more than 8,600 girls. And public health poster abstracts at HPV2014 presented new research on everything from factors impacting HPV vaccine uptake among high school students (physicians were encouraged to take a more active role in advocating for vaccination) to whether a two-dose approach in 9- to 13-year old girls would be influenced by age, body-mass index or whether they had started their period. The abstracts also included one study that explored the effectiveness of just a single dose of the HPV vaccine.

"My own perspective is that HPV vaccines currently offer one of the most promising approaches to reducing cancer morbidity and mortality in the developing world," said Dr. Garnet Anderson, director of Fred Hutch's Public Health Sciences division. "Any advancement that reduces the cost of broadly implementing an HPV vaccination program without substantial loss of efficacy could have a major public health benefit."

Overcoming stigma, saving lives

Danah Abarr, founder and president of HPV Hope, a nonprofit that offers support, resources and education around HPV and HPV-related cancers, said she’s encouraged by all the recent scientific innovations.

“It’s really exciting to see such active research around such a highly stigmatized topic,” she said. “The vaccine continues to grow in terms of its development. And it’s going to continue to grow and develop and get better.”

But she also pointed out that education and awareness need to grow, too, regardless of the doses teens and tweens receive, a sentiment echoed recently in a New York Times editorial encouraging doctors to take a more active role in boosting HPV awareness.

“Until we can have open conversations and be more knowledgeable and make parents more knowledgeable, it’s going to be difficult to see the vaccination rates increase,” she said. “Vaccines have their own stigma, in general, and layered on top of that, you have a vaccine for an STI. It’s a hurdle to overcome. It all comes back to us as a society being able to have open conversations about difficult topics.”

Diane Mapes is a staff writer at Fred Hutchinson Cancer Research Center. She has also written extensively about health issues for nbcnews.com, TODAY.com, CNN.com, MSN.com, Columns and several other publications. She also writes the breast cancer blog, doublewhammied.com.Reach her at dmapes@fredhutch.org.

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Solid tumors, such as those of the cervix, are the focus of Solid Tumor Translational Research, a network comprised of Fred Hutchinson Cancer Research Center, UW Medicine and Seattle Cancer Care Alliance. STTR is bridging laboratory sciences and patient care to provide the most precise treatment options for patients with solid tumor cancers.